4,4-Disubstituted spiro-1,4-dihydropyridines and a process for their production

Abstract

The invention relates to 4,4-disubstituted spiro-1,4-dihydropyridine compounds of formula (I). Also included in the invention are methods for producing the compounds of formula (I) by (a) cyclizing a compound of formula (II) in the presence of a base or (b) reducing a sulphinyl compound of formula (I) by means of Raney nickel. The compounds of formula I are intermediates and can be converted to sulphur-free compounds of formula (III) which are known to be useful for treating circulatory illnesses.

What is claimed is: 
     
       1. A compound of the formula ##STR14## in which  A  represents a monocyclic or bicyclic carbocyclic aryl radical or a heterocyclic radical selected from furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, quinazolyl or quinoxalyl, the said aryl radical or heterocyclic radical being unsubstituted or containing 1, 2 or 3 identical or different substituents selected from phenyl, C 1  -C 8  -alkyl, C 1  -C 8  -alkenyl, C 1  -C 8  -alkinyl, C 1  -C 8  -alkoxy, C 1  -C 6  -alkylene, C 1  -C 4  -dioxyalkylene, halogen, trifluoromethyl, trifluoromethoxy, C 1  -C 4  -alkylamino, nitro, cyano, azido and carboxamido, R 3  and R 4  are identical or different and each represent a hydrogen atom or an achiral straight-chain or branched C 1  -C 8  -alkyl radical, a monocyclic or bicyclic carbocyclic aryl radical or a monocyclic or bicyclic carbocyclic aryl-C 1  -C 4  -alkyl radical, said aryl and aralkyl radicals being unsubstituted or substituted by 1, 2 or 3 identical or different substituents selected from phenyl, C 1  -C 8  -alkyl, C 1  -C 8  -alkenyl, C 1  -C 8  -alkinyl, C 1  -C 8  -alkoxy, C 1  -C 6  -alkylene, C 1  -C 4  -dioxyalkylene, halogen, trifluoromethyl, trifluoromethoxy, C 1  -C 4  -alkylamino, nitro, cyano, azido and carboxamido on the aryl nucleus and containing 1 to 2 carbon atoms in the alkyl portion,   R 2  and R 5  are identical or different and each represent a straight-chain or branched C 1  -C 8  -alkyl radical, which is optionally interrupted in the chain by oxygen and is optionally substituted by halogen, pyridyl, phenyl or phenoxy, the phenyl or phenoxy group optionally being substituted by halogen, cyano, di-C 1  -C 4  -alkylamino, C 1  -C 4  -alkoxy, C 1  -C 4  -alkyl, trifluoromethyl or nitro,   R 1  represents a straight-chain or branched C 1  -C 8  -alkyl radical which is optionally interrupted in the chain by one oxygen and is optionally substituted by phenyl, phenoxy, pyridyl or amino, the phenyl, phenoxy or pyridyl radicals optionally being substituted by halogen, cyano, di-C 1  -C 4  -alkylamino, C 1  -C 4  -alkoxy, C 1  -C 4  -alkyl, trifluoromethyl or nitro, and the amino group optionally being substituted by two identical or different substituents selected from C 1  -C 4  -alkyl, C 1  -C 4  -alkoxy-C 1  -C 4  -alkyl, a monocyclic or bicyclic carbocyclic aryl and a monocyclic or bicyclic carbocyclic aryl-C 1  -C 4  -alkyl radical and   n is 0, 1 or 2.   
     
     
       2. A compound according to claim 1, in which A represents a phenyl, naphthyl, furyl, pyrryl or pyridyl radical optionally containing 1, 2 or 3 identical or different substituents selected from phenyl, alkyl, alkenyl, alkinyl, alkoxy, alkylene, dioxyalkylene and alkylamino with in each case up to 4 carbon atoms, in each alkyl, alkenyl, alkinyl or alkoxy group, C 1  -C 6  -alkylene, C 1  -C 4  -dioxyalkylene, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano, azido and carboxamido,   R 3  and R 4  are identical or different and each represent a hydrogen atom or an alkyl radical with up to 4 carbon atoms, a phenyl radical or a benzyl radical,   R 2  and R 5  are identical or different and each represent a straight-chain or branched C 1  -C 8  -alkyl radical, which is optionally interrupted in the chain by oxygen and is optionally substituted by halogen, pyridyl, phenyl or phenoxy, the phenyl or phenoxy group optionally being substituted by halogen, cyano, di-C 1  -C 4  -alkylamino, C 1  -C 4  -alkoxy, C 1  -C 4  -alkyl, trifluoromethyl or nitro,   R 1  represents a straight-chain or branched C 1  -C 8  -alkyl radical which is optionally interrupted in the chain by one oxygen and is optionally substituted by phenyl, phenoxy, pyridyl or amino, the phenyl, phenoxy or pyridyl radicals optionally being substituted by halogen, cyano, di-C 1  -C 4  -alkylamino, C 1  -C 4  -alkoxy, C 1  -C 4  -alkyl, trifluoromethyl or nitro, and the amino group optionally being substituted by two identical or different substituents selected from C 1  -C 4  -alkyl, C 1  -C 4  -alkoxy-C 1  -C 4  -alkyl, a monocyclic or bicyclic carbocyclic aryl and a monocyclic or bicyclic carbocyclic aryl-C 1  -C 4  -alkyl radical and   n is 0, 1 2.   
     
     
       3. A compound according to claim 1, in which  A  represents a phenyl, furyl, pyrryl or pyridyl radical optionally containing 1 or 2 identical or different substituents selected from phenyl, alkyl, alkoxy and alkyl-amino, with in each case 1 to 4 carbon atoms in the alkyl or alkoxy radicals, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano and azido,   R 3  and R 4  are identical or different and each represent a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms or a phenyl or benzyl radical,   R 2  and R 5  are identical or different and each represent an alkyl radical which has 1 to 6 carbon atoms, and which is optionally interrupted in the chain by oxygen or is optionally substituted by halogen or phenyl,   R 1  represents alkyl or alkinyl with up to 6 carbon atoms, the alkyl radical optionally being interrupted in the chain by one oxygen and optionally being substituted by phenyl, phenoxy or amino, and the amino group optionally being substituted by two identical or different substituents selected from alkyl with 1 to 4 carbon atoms, phenyl and benzyl, and   n is 0 or 1.   
     
     
       4. A compound according to claim 1 which is 4,3'-Spiro[2,6-dimethyl-3,5-bis-methoxycarbonyl-1,4-dihydropyridine]-[2'3'-dihydro-1'-benzothiophene-1'-oxide]. 
     
     
       5. A compound according to claim 1 which is 4,3'-Spiro[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridine]-5'-nitro-[2',3'-dihydro-1'-benzothiophene-1'-oxide]. 
     
     
       6. A compound according to claim 1 which is 4,3'-Spiro[2,6-dimethyl-3,5-bisethoxycarbonyl-1,4-dihydropyridine]-[2',3'-dihydro-thieno-[2.3-b]-pyridine-1'-oxide]. 
     
     
       7. A compound according to claim 1 which is 4,4'-Spiro-[2,6-dimethyl-3,5-bismethoxycarbonyl-1,4-dihydropyridine]-2'-methyl-[2',3'-dihydro-1'-benzothiophene-1'-oxide]. 
     
     
       8. A compound according to claim 1 which is 4,3'-Spiro[2,6-dimethyl-3,5-bismethoxy-carbonyl-1,4-dihydropyridine]-[2',3'-hydro-1'-benzothio-phene]. 
     
     
       9. A process for the production of a compound according to claim 1, which comprises cyclizing (a) a pyridine of the formula ##STR15##  in which R 1 , R 2 , R 3 , R 4 , R 5 , n and A have same meanings as in claim 1, at a temperature between -120° C. and +30° C. in the presence of a base to give a spiro compound of claim 1, and   (b) if a compound of claim 1 in which n is 0 is desired and the product of reaction variant (a) is a sulphinyl compound, reducing said sulphinyl compound by means of Raney nickel.   
     
     
       10. A process according to claim 9, in which reaction variant (a) is carried out in the presence of an inert organic solvent. 
     
     
       11. A process according to claim 9, in which reaction variant (a) is carried out in a temperature range from -90° to -40° C. 
     
     
       12. A process according to claim 9, 10 or 11 in which the cyclization is carried out in the presence of a 2- to 3- fold excess of base.